A protein group called ubiquitin-like protein (Ubl), typified by ubiquitin, binds to corresponding activating enzyme E1 and transferase E2 to be added to a target protein through a covalent bond, thereby exerting influences on various characteristics such as target enzyme activity, stability, intracellular localization, and the like (Non-patent Document 1).
Nedd8, a kind of Ubl, is activated by APPBP1-UBA3 heterodimer, which is a Nedd8-activating enzyme (NAE), in an ATP-dependent manner. The activated Nedd8 is subsequently transferred to E2 (Ubc12), and is then added to a series of target proteins called cullin. It is called neddylation that Nedd8 is conjugated to a target protein. The neddylation with respect to cullin promotes the activity (ability to add ubiquitin to a ligase substrate) of cullin-RING ligases (CRL), which function by forming a complex with cullin family protein and adaptor protein. The protein group ubiquitinated by CRL is degraded in the proteasome. Many proteins are known as CRL substrates that regulate cell cycles and conduct intracellular signal transduction, and that are reported to be decreased expression in tumors; examples of such proteins include p27, p21, and phosphorylated Ik-B (Non-patent Documents 2 and 3). More specifically, NAE contributes to tumor cell growth and survival by facilitating ubiquitination and degradation by proteasome of the CRL substrate protein group through Nedd8 activation.
Because of the physiological function of NAE, an NAE inhibitor has a characteristic property of simultaneously affecting a plurality of signaling pathways involved in the survival and growth of tumors. Thus, NAE inhibitors are expected to serve as a therapeutic agent having broad and effective antitumor actions. N-[(1S)-1-indanyl]-7-[(1R)-3α-hydroxy-4α-(sulfamoyloxymethyl)cyclopentyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (hereinafter referred to as “MLN4924”) and the like have been known as a compound that inhibits the Nedd8-activating function of NAE (Patent Document 1). MLN4924 is a compound having a pyrrolopyrimidine skeleton, and is characterized by having a substituted amino group at 4-position. MLN4924 causes accumulation of the CRL substrate protein group through neddylation inhibition, thereby inducing cell growth arrest and apoptosis (Non-patent Document 4). Currently, the development of MLN4924 as an antitumor agent has been advanced (Patent Document 2); and, in addition to the use of MLN4924 alone, tests using a combination of MLN4924 and other various anticancer drugs have also been conducted (Non-patent Documents 5 and 6). However, a great deal of the MLN4924 administered is transferred to red blood cells in the blood; thus, an issue of decrease in plasma concentration from the concentration required for ensuring the original medicinal effects of MLN4924 has been identified (Non-patent Document 6). Further, since MLN4924 inhibits carbonic anhydrase II, which is highly expressed even in normal organs, such as red blood cells, kidneys, brain, and eyes, there is a concern that MLN4924 induces side effects, specifically, electrolyte abnormality, hypotonia bulbi, metabolic acidosis, polyuria, urinary calculus, and dysesthesia (Non-patent Document 8). Under such circumstances, a new NAE inhibitor that ensures NAE inhibitory activity, but that has a smaller carbonic anhydrase II inhibitory effect, has been desired.